CN103275311A - Polylactide-loaded prodrug and preparation method thereof - Google Patents

Polylactide-loaded prodrug and preparation method thereof Download PDF

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CN103275311A
CN103275311A CN2013101810552A CN201310181055A CN103275311A CN 103275311 A CN103275311 A CN 103275311A CN 2013101810552 A CN2013101810552 A CN 2013101810552A CN 201310181055 A CN201310181055 A CN 201310181055A CN 103275311 A CN103275311 A CN 103275311A
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polylactide
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carboxyl
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CN103275311B (en
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张雪飞
麻戈军
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Xiangtan University
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Abstract

The invention discloses a polylactide-loaded prodrug and a preparation method thereof. The preparation method comprises the following steps of: carrying out a sulfhydryl-alkene click chemical reaction on a functionalized polylactide with a lateral group containing norbornene and a sulfhydryl compound to obtain polylactide containing a hydroxyl side group or carboxyl group; and carrying out an esterification reaction on the polylactide containing the hydroxyl side group or carboxyl group and drug molecules to obtain the prodrug. The prodrug prepared by using the preparation method is large and controllable in drug loading capacity, good in hydrophily and completely degradable; and the preparation method is simple, economical, highly-efficient and non-toxic.

Description

Polylactide loaded prodrug and preparation method thereof
Technical Field
The invention relates to a polylactide loaded prodrug and a preparation method thereof, belonging to the field of drug modification.
Background
Prodrugs are compounds which, after oral administration, are metabolized chemically or enzymatically in vivo to release the pharmacologically active metabolite or prodrug. The method is to connect the original drug and a carrier through chemical bonds to form a temporary chemical combination or a covering, thereby changing or modifying the physicochemical property of the original drug, and then degrading the original drug in vivo to exert the drug effect. This in turn can be said to be a carrier prodrug. Since the 20 th century and the 50 th century, the concept plays a great role in the structural modification and the chemical development of drugs, and becomes an important means for the design and development of drugs in the 21 st century.
The small molecular active medicine is fixed by the polymer, and then slowly released in vivo to play a role, has the characteristics of long acting, slow release and the like, and meanwhile, the high molecular medicine can be endocytosed by cells and is easily taken by tumor cells, so that the small molecular active medicine has a function of directional action. And the traditional micromolecule antitumor drugs have the defects of large toxic and side effects, low drug effective utilization rate and membrane permeation capability, lack of ideal specific ligands, need of frequent administration and the like, and are limited in clinical application. Thus, the traditional administration mode of the high-molecular prodrug is changed.
The development of a prodrug is actually the development of a carrier, and a good polymeric prodrug carrier should meet the following requirements: 1) active functional groups such as carboxyl, hydroxyl, sulfhydryl, amino and the like; 2) the biocompatibility is good, no toxicity exists, and no immunogenicity exists; 3) good biodegradability and molecular weight below renal excretion values; 4) practicality, easily available raw materials. Therefore, the selection of the polymer modifier is the key for modifying drug molecules, and aliphatic polyesters such as polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) and poly epsilon-caprolactone (PCL) belong to biodegradable polymers; it is emphasized that its molecular weight can be controlled in a relatively wide range.
Aliphatic polyesters represented by Polylactide (PLA) are a few biomedical materials which are approved by the American FDA and have the advantages of good biocompatibility and biodegradability, but have a single chemical structure, and a high-molecular main chain lacks functional groups capable of being further bonded with drugs and bioactive substances, so that in order to solve the problems, hydrophilic groups with reactivity are necessarily introduced into side chains of polylactide, so that a polymer drug carrier which can be compared with polyglutamic acid, namely a drug carrier with hydrophilicity, degradability and good biocompatibility, is obtained, and effective bonding of drug molecules, target molecules and quantum dots is realized by utilizing the functional groups with reactivity; obtaining such a prodrug loaded with a carrier polymer has great scientific and economic value significance.
Disclosure of Invention
Aiming at the defects that the biomedical material of PLA in the prior art has single chemical structure, poor water solubility and the lack of active functional groups capable of being further bonded with drugs and bioactive substances on a high-molecular main chain, the invention aims to provide the polylactide-loaded prodrug which has good hydrophilicity, can be completely biodegraded, has high and controllable drug loading capacity and high purity and contains a modifiable group.
It is another object of the present invention to provide an economical, efficient and non-toxic method for preparing the above polylactide-loaded prodrugs.
The invention provides a polylactide loaded prodrug, which has a structure of formula 1, formula 2 or formula 3:
Figure BDA00003197423100021
wherein,
x is 0-100, y is 1-100; x1 is 0-100, y1+ z1 is 1-100;
n is 10 to 100;
R1is C1～C3One of the alkoxy groups of (a);
R2is composed of
Figure BDA00003197423100031
m is 1-5;
R3is composed of
Figure BDA00003197423100032
r is 2-5;
in formula 3:
R4is composed of
Figure BDA00003197423100033
R5Is composed of
Figure BDA00003197423100034
And/or
Figure BDA00003197423100035
R6Is composed of
Figure BDA00003197423100036
Or R4Is composed ofR5Is composed of
Figure BDA00003197423100038
And/or
Figure BDA00003197423100039
R6Is composed of
Figure BDA000031974231000310
Or R4Is composed of
Figure BDA000031974231000311
R5Is composed of
Figure BDA000031974231000312
And/or
Figure BDA000031974231000313
R6Is composed of
Figure BDA000031974231000314
Or R4Is composed of
Figure BDA000031974231000315
R5Is composed of
Figure BDA000031974231000316
And/or
Figure BDA000031974231000317
R6Is composed of
Figure BDA000031974231000318
Or R4Is composed ofR5Is composed ofAnd/or
Figure BDA000031974231000321
R6Is composed of
Figure BDA000031974231000322
Or R4Is composed of
Figure BDA000031974231000323
R5Is composed ofAnd/or
Figure BDA000031974231000325
R6Is composed of
Figure BDA000031974231000326
D is a group generated after esterification reaction of a drug molecule containing hydroxyl and polylactide containing a carboxyl side group;
and B is a group generated after esterification reaction of a medicament molecule containing carboxyl and polylactide containing a hydroxyl side group.
Preferred prodrugs have the structure of formula 1, formula 2 or formula 3, wherein R1Is C1～C3One of the alkoxy groups of (a); r2Is composed of
Figure BDA000031974231000327
m is 1-5; r3Is composed of
Figure BDA000031974231000328
r is 2-5; in formula 3: r4Is composed of
Figure BDA000031974231000329
R5Is composed of
Figure BDA000031974231000330
And/or
Figure BDA000031974231000331
R6Is composed of
Figure BDA000031974231000332
Or R4Is composed of
Figure BDA000031974231000333
R5Is composed of
Figure BDA000031974231000334
And/or
Figure BDA000031974231000335
R6Is composed ofOr R4Is composed of
Figure BDA000031974231000337
R5Is composed of
Figure BDA000031974231000338
And/or
Figure BDA000031974231000339
R6Is composed of
Figure BDA000031974231000340
More preferred prodrugsHas a structure of formula 1, formula 2 or formula 3, wherein R1Is one of methoxy, ethoxy or propoxy; r2Is composed of
Figure BDA00003197423100041
m is 1-5; r3Is composed of
Figure BDA00003197423100042
r is 2-5; r in the formula 34Is composed of
Figure BDA00003197423100043
R5Is composed of
Figure BDA00003197423100044
And/or
Figure BDA00003197423100045
R6Is composed of
Figure BDA00003197423100046
Or R4Is composed of
Figure BDA00003197423100047
R5Is composed of
Figure BDA00003197423100048
And/or
Figure BDA00003197423100049
R6Is composed of
Figure BDA000031974231000410
Or R4Is composed of
Figure BDA000031974231000411
R5Is composed of
Figure BDA000031974231000412
And/orR6Is composed of
Figure BDA000031974231000414
The hydroxyl-containing drug molecules are one or more of paclitaxel, docetaxel, adriamycin or camptothecin.
The drug molecules containing carboxyl are one or more of aspirin, fenbufen and ketoprofen.
The invention also provides a preparation method of the prodrug, which comprises the steps of carrying out mercapto-alkene click chemical reaction on the polylactide with the side group containing norbornene functionalization and a mercapto compound to obtain the polylactide containing the hydroxyl side group or the carboxyl side group; carrying out esterification reaction on the obtained polylactide containing the hydroxyl side group or the carboxyl side group and drug molecules to obtain the compound; the mercapto compound has the structure of formula 4:
HS-R7
formula 4
Wherein R is7Is one of 5-carboxypentyl group, 4-carboxybutyl group, 3-carboxypropyl group, 2-carboxyethyl group, carboxylic acid methyl group, 5-hydroxypentyl group, 4-hydroxybutyl group, 3-hydroxypropyl group, 2-hydroxyethylyl group, 4, 5-dihydroxypentyl group, 3, 5-dihydroxypentyl group, 2, 5-dihydroxypentyl group, 3, 4-dihydroxybutyl group, 2, 4-dihydroxybutyl group or 2, 3-dihydroxypropyl group.
The drug molecules are one or more of paclitaxel, docetaxel, adriamycin and camptothecin, or one or more of aspirin, fenbufen and ketoprofen.
The sulfydryl-alkene click chemical reaction is carried out under ultraviolet light of 250-400 nm.
One or more of 1-hydroxycyclohexyl phenyl ketone, benzophenone, 2-methyl benzophenone, 4-phenyl benzophenone, 3, 4-dimethyl benzophenone, 4' -bis (diethylamino) benzophenone, benzoin methyl ether, benzoin dimethyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin n-butyl ether or benzoin isobutyl ether is/are added into the sulfydryl-alkene click chemistry reaction to serve as a photosensitizer.
The reaction time of the sulfydryl-alkene click chemistry is 1-12 h.
The esterification reaction is that in the presence of a condensing agent dicyclohexylcarbodiimide and an organic amine catalyst pyridine, triethylamine or N, N-dimethyl-p-aminopyridine, polylactide containing a hydroxyl side group and a medicament molecule containing a carboxyl are subjected to esterification reaction at 0-30 ℃ in THF or dichloromethane; or the esterification reaction is carried out between the polylactide containing the carboxyl side group and the drug molecule containing the hydroxyl under the conditions at 0-30 ℃ to obtain the prodrug loaded by the polylactide.
The molar consumption of the condensing agent dicyclohexylcarbodiimide is 1-2 times of that of the carboxyl participating in the reaction; the molar dosage of the organic amine catalyst is 0.5-2 times of that of the carboxyl group participating in the reaction.
The preparation method of the polylactide with the side group containing norbornene functionalization comprises the following steps: carrying out substitution reaction on lactide and N-bromosuccinimide (NBS) in carbon tetrachloride or benzene solution at 60-90 ℃ under the catalytic action of dibenzoyl peroxide (BPO) to obtain bromolactide; carrying out elimination reaction on the obtained bromolactide in a dichloromethane solvent under the action of triethylamine at 0-5 ℃ to obtain double-bond lactide; carrying out Diels-Alder reaction on the obtained double-bond lactide and freshly distilled cyclopentadiene in a carbon tetrachloride or benzene solution at the temperature of 60-90 ℃ to obtain lactide containing norbornene side groups; TBD or DBU is used as a catalyst, dichloromethane is used as a solvent, ring opening polymerization is carried out at-20-40 ℃, and then the norbornene functionalized polylactides are obtained.
The invention has the beneficial effects that: according to the invention, a large number of hydroxyl groups or carboxyl groups are introduced into the side chains of the polylactide, so that a large number of sites are provided for the key bonding of drug molecules, and the economic, efficient and nontoxic polylactide-loaded prodrug which has large and controllable drug-loading capacity and can be completely degraded is prepared; the preparation method is simple, safe and nontoxic, has low cost and good application prospect.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the poly (lactide) functionalized by the norbornene in example 1.
FIG. 2 is a nuclear magnetic hydrogen spectrum of polylactide containing pendant monohydroxy functional groups of example 1.
Figure 3 is a nuclear magnetic hydrogen spectrum of the polylactide-loaded aspirin prodrug of example 1.
FIG. 4 is a nuclear magnetic hydrogen spectrum of polylactide containing pendant dihydroxy functional groups of example 2.
Fig. 5 is a nuclear magnetic hydrogen spectrum of the polylactide-loaded aspirin prodrug of example 2.
FIG. 6 is a nuclear magnetic hydrogen spectrum of polylactide containing pendant monocarboxylic functional groups of example 3.
FIG. 7 is a nuclear magnetic hydrogen spectrum of the polylactide-loaded paclitaxel prodrug of example 3.
FIG. 8 is a gel chromatogram of polylactide containing pendant monohydroxy functional groups and polylactide-loaded aspirin prodrug of example 1: a polylactide containing pendant monohydroxy functional groups; b is a polylactide-loaded aspirin prodrug.
FIG. 9 is a gel chromatogram of the polylactide containing pendant dihydroxy functional groups and the polylactide-loaded aspirin prodrug of example 2: a is a polylactide containing pendant dihydroxy functional groups; b is a polylactide-loaded aspirin prodrug.
FIG. 10 is a gel chromatogram of polylactide containing pendant monocarboxylic functionality and polylactide-loaded paclitaxel prodrug of example 3: a is polylactide containing pendant monocarboxylic functional groups; b is a polylactide-loaded paclitaxel prodrug.
FIG. 11 is an infrared spectrum of polylactide containing pendant monohydroxy functional groups and polylactide-loaded aspirin prodrug of example 1: a polylactide containing pendant monohydroxy functional groups; b is a polylactide-loaded aspirin prodrug.
FIG. 12 is an infrared spectrum of polylactide containing pendant dihydroxy functional groups and polylactide-loaded aspirin prodrugs of example 2: a is a polylactide containing pendant dihydroxy functional groups; b is a polylactide-loaded aspirin prodrug.
FIG. 13 is an infrared spectrum of polylactide containing pendant monocarboxylic functionality and polylactide-loaded paclitaxel prodrugs of example 3: a is polylactide containing pendant monocarboxylic functional groups; b is a polylactide-loaded paclitaxel prodrug.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1
1. Preparation of polylactide containing pendant monohydroxy functional groups:
0.100g (double bond: 0.00048 mol) of a side norbornene-functionalized polylactide (see FIG. 1 for nuclear magnetic resonance) was completely dissolved in 8mL of Tetrahydrofuran (THF) under the protection of nitrogen, 0.187g (0.0024 mol) of mercaptoethanol was added, 1-hydroxycyclohexyl phenyl ketone (photoinitiator 184) dissolved in 2mL of THF was added thereto, and the reaction was carried out at room temperature under an ultraviolet lamp with a wavelength of about 365nm for 1 hour, after the reaction was completed, THF was removed by spinning, methylene chloride was dissolved, and the solution was precipitated in ether to obtain a side monohydroxy functional group-containing polylactide. The structural representation is shown in a nuclear magnetic hydrogen spectrum (figure 2), an infrared graph (figure 11 a) and a molecular weight distribution (figure 8 a), which indicate that the polymer is successfully synthesized.
2. Preparation of polylactide-loaded aspirin prodrugs:
in a 25mL reaction flask, 0.100g (hydroxyl group: 0.00035 mol) of polylactide having a monohydroxy functional group on the side was dissolved in 5mL of methylene chloride, 0.063g (0.00035 mol) of aspirin was added, a solution of 0.099g (0.00035 mol) of DCC in methylene chloride was further added to the reaction system, a catalytic amount of DMAP was further added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, insoluble matter was removed by filtration. The dichloromethane is removed by spinning, a small amount of DMF is added to dissolve the dichloromethane, and the solution is placed in a dialysis bag (3500K) to be dialyzed in secondary water for 48 hours to obtain the polylactide-loaded aspirin prodrug. The structural representation is shown in a nuclear magnetic hydrogen spectrum chart (figure 3), an infrared chart (figure 11 b) and a molecular weight distribution chart (figure 8 b), which indicate that the polymer has been successfully synthesized.
Example 2
1. Preparation of polylactide containing pendant dihydroxy functional groups:
under the protection of nitrogen, 0.100g (double bond: 0.00048 mol) of the side norbornene functionalized polylactide is completely dissolved in 8mL of THF, then 0.259g (0.0024 mol) of 3-mercapto-1, 2-propanediol is added, then 1-hydroxycyclohexyl phenyl ketone dissolved with 2mL of THF is added, the reaction is carried out for 1h at room temperature under the illumination of an ultraviolet lamp with the wavelength of 365nm, after the reaction is finished, THF is spun off, crude product is obtained by sedimentation in ether, then the crude product is dissolved with a small amount of DMF, and the crude product is placed in a dialysis bag (3500K) to be dialyzed in secondary water for 48h, thus obtaining the polylactide containing the side dihydroxy functional group. The structural representation is shown in a nuclear magnetic hydrogen spectrum chart (figure 4), an infrared chart (figure 12 a) and a molecular weight distribution chart (figure 9 a), which indicate that the polymer has been successfully synthesized.
2. Preparation of polylactide-loaded aspirin prodrugs:
0.100g (hydroxyl: 0.00063 mol) of a bishydroxy functional polylactide on the side was dissolved in 5mL of THF in a 25mL reaction flask, 0.114g (0.00063 mol) of aspirin was added, and a solution of 0.130g (0.00063 mol) of DCC in THF was added to the reaction system, and a catalytic amount of DMAP was further added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, insoluble matter was removed by filtration. THF is removed, a small amount of DMF is added to dissolve the solution, and the solution is placed in a dialysis bag (3500K) to be dialyzed in secondary water for 48 hours to obtain the polylactide-loaded aspirin prodrug. The structural representation is shown in a nuclear magnetic hydrogen spectrum chart (figure 5), an infrared chart (figure 12 b) and a molecular weight distribution chart (figure 9 b), which indicate that the polymer has been successfully synthesized.
Example 3
1. Preparation of polylactide containing pendant monocarboxylic functional groups:
under the protection of nitrogen, 0.100g (double bond: 0.00048 mol) of the side norbornene functionalized polylactide is completely dissolved in 8mL of THF, then 0.254g (0.0024 mol) of mercaptoethanol is added, then 1-hydroxycyclohexyl phenyl ketone dissolved in 2mL of THF is added, the reaction is carried out for 1h at room temperature under the illumination of an ultraviolet lamp with the wavelength of 365nm, after the reaction is finished, THF is removed, DMF is dissolved, and the solution is precipitated in ether, thus obtaining the polylactide containing side monocarboxylic functional groups. The structural representation is shown in a nuclear magnetic hydrogen spectrum chart (figure 6), an infrared chart (figure 13 a) and a molecular weight distribution chart 10a, which indicate that the polymer has been successfully synthesized.
2. Preparation of polylactide-loaded paclitaxel prodrug:
in a 25mL reaction flask, 0.100g (carboxyl: 0.00029 mol) of a single carboxyl functional group-pendant polylactide was dissolved in 5mL of THF, 0.050g (0.000059 mol) of paclitaxel was added, and a solution of 0.012g (0.000059 mol) of DCC in THF was added to the reaction system, and a catalytic amount of DMAP was added thereto, followed by stirring at room temperature for 24 hours. After the reaction is finished, insoluble substances are removed by filtration, THF is spun off, a small amount of DMF is added and placed in a dialysis bag (3500K) to be dialyzed in secondary water for 48 hours, and the polylactide-loaded taxol prodrug is obtained. The structural representation is shown in a nuclear magnetic hydrogen spectrum chart (figure 7), an infrared chart (figure 13 b) and a molecular weight distribution chart 10b, which indicate that the polymer has been successfully synthesized.

Claims (6)

1. A polylactide-loaded prodrug having the structure of formula 1, formula 2, or formula 3:
wherein,
x is 0-100, y is 1-100; x1 is 0-100, y1+ z1 is 1-100;
n is 10 to 100;
R1is C1～C3One of the alkoxy groups of (a);
R2is composed of
Figure FDA00003197423000012
m is 1-5;
R3is composed of
Figure FDA00003197423000013
r is 2-5;
in formula 3:
R4is composed of
Figure FDA00003197423000021
R5Is composed of
Figure FDA00003197423000022
And/or
Figure FDA00003197423000023
R6Is composed of
Or R4Is composed of
Figure FDA00003197423000025
R5Is composed of
Figure FDA00003197423000026
And/or
Figure FDA00003197423000027
R6Is composed of
Figure FDA00003197423000028
Or R4Is composed of
Figure FDA00003197423000029
R5Is composed ofAnd/or
Figure FDA000031974230000211
R6Is composed of
Figure FDA000031974230000212
Or R4Is composed of
Figure FDA000031974230000213
R5Is composed of
Figure FDA000031974230000214
And/or
Figure FDA000031974230000215
R6Is composed of
Figure FDA000031974230000216
Or R4Is composed of
Figure FDA000031974230000217
R5Is composed of
Figure FDA000031974230000218
And/or
Figure FDA000031974230000219
R6Is composed of
Figure FDA000031974230000220
Or R4Is composed of
Figure FDA000031974230000221
R5Is composed of
Figure FDA000031974230000222
And/or
Figure FDA000031974230000223
R6Is composed of
D is a group generated after esterification reaction of a drug molecule containing hydroxyl and polylactide containing a carboxyl side group;
and B is a group generated after esterification reaction of a medicament molecule containing carboxyl and polylactide containing a hydroxyl side group.
2. The prodrug of claim 1 in which R in formula 34Is composed of
Figure FDA000031974230000225
R5Is composed ofAnd/or
Figure FDA000031974230000227
R6Is composed of
Figure FDA000031974230000228
Or R4Is composed of
Figure FDA000031974230000229
R5Is composed of
Figure FDA000031974230000230
And/or
Figure FDA000031974230000231
R6Is composed of
Figure FDA000031974230000232
Or R4Is composed of
Figure FDA000031974230000233
R5Is composed ofAnd/or
Figure FDA000031974230000235
R6Is composed of
3. The prodrug of claim 2 in which R1Is one of methoxyl, ethoxyl or propoxyl.
4. The prodrug of claim 1, wherein the hydroxyl-containing drug molecule is one or more of paclitaxel, docetaxel, doxorubicin, or camptothecin; the drug molecules containing carboxyl are one or more of aspirin, fenbufen and ketoprofen.
5. A process for the preparation of a prodrug as claimed in any one of claims 1 to 4, wherein a norbornene-functionalized polylactide containing pendant groups is subjected to a thiol-ene click chemistry reaction with a thiol compound to give a polylactide containing pendant hydroxyl or carboxyl groups; carrying out esterification reaction on the obtained polylactide containing the hydroxyl side group or the carboxyl side group and drug molecules to obtain the compound; the mercapto compound has the structure of formula 4:
HS-R7
formula 4
Wherein R is7Is 5-carboxypentyl, 4-carboxybutyl, 3-carboxypropyl, 2-carboxyethyl, carboxylic acid methyl, 5-hydroxyOne of a pivaloyl group, a 4-hydroxybutyl group, a 3-hydroxypropanyl group, a 2-hydroxyethylyl group, a 4, 5-dihydroxypentyl group, a 3, 5-dihydroxypentyl group, a 2, 5-dihydroxypentyl group, a 3, 4-dihydroxybutyl group, a 2, 4-dihydroxybutyl group or a 2, 3-dihydroxypropyl group.
6. The method of claim 5, wherein the drug molecule is one or more of paclitaxel, docetaxel, doxorubicin, and camptothecin, or one or more of aspirin, fenbufen, and ketoprofen.
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CN105251013A (en) * 2015-09-28 2016-01-20 湘潭大学 Degradable water-soluble antitumor polymer prodrug with redox responsiveness and preparation method thereof
CN106177978A (en) * 2016-07-18 2016-12-07 湘潭大学 A kind of antitumor polymer bond drug with targeting and tracking function and preparation method thereof
CN106177980A (en) * 2016-07-18 2016-12-07 湘潭大学 A kind of amphipathic nature polyalcohol anti-tumor predrug with quantum dot tracking function and preparation method thereof
CN111410735A (en) * 2019-01-08 2020-07-14 上海深竹化工科技有限公司 Water-soluble fluorine-containing block polymer, preparation method and application thereof
CN111410737A (en) * 2019-01-08 2020-07-14 上海深竹化工科技有限公司 Polyester type fluorine-containing block polymer, preparation method and application thereof

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CN101543632A (en) * 2008-11-20 2009-09-30 湘潭大学 Anti-tumor prodrug having accurate structure and taking novel amphipathic polymer as carrier and synthetic method thereof

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CN101543632A (en) * 2008-11-20 2009-09-30 湘潭大学 Anti-tumor prodrug having accurate structure and taking novel amphipathic polymer as carrier and synthetic method thereof

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CN105251013A (en) * 2015-09-28 2016-01-20 湘潭大学 Degradable water-soluble antitumor polymer prodrug with redox responsiveness and preparation method thereof
CN105251013B (en) * 2015-09-28 2018-08-14 湘潭大学 One kind having degradable water-soluble antitumor polymeric prodrugs of redox response and preparation method thereof
CN106177978A (en) * 2016-07-18 2016-12-07 湘潭大学 A kind of antitumor polymer bond drug with targeting and tracking function and preparation method thereof
CN106177980A (en) * 2016-07-18 2016-12-07 湘潭大学 A kind of amphipathic nature polyalcohol anti-tumor predrug with quantum dot tracking function and preparation method thereof
CN106177980B (en) * 2016-07-18 2019-04-09 湘潭大学 A kind of amphiphilic polymer anti-tumor predrug and preparation method thereof with quantum dot tracking function
CN106177978B (en) * 2016-07-18 2019-04-09 湘潭大学 A kind of antitumor polymer bond drug and preparation method thereof with targeting and tracking function
CN111410735A (en) * 2019-01-08 2020-07-14 上海深竹化工科技有限公司 Water-soluble fluorine-containing block polymer, preparation method and application thereof
CN111410737A (en) * 2019-01-08 2020-07-14 上海深竹化工科技有限公司 Polyester type fluorine-containing block polymer, preparation method and application thereof
CN111410735B (en) * 2019-01-08 2021-04-02 上海深竹化工科技有限公司 Water-soluble fluorine-containing block polymer, preparation method and application thereof

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